Radium-223 Dichloride and Abiraterone Acetate Compared to Placebo and Abiraterone Acetate for Men With Cancer of the Prostate When Medical or Surgical Castration Does Not Work and When the Cancer Has Spread to the Bone, Has Not Been Treated With Chemotherapy and is Causing no or Only Mild Symptoms

Phase 3CompletedNCT02043678

Bayer806 enrolled

Overview

To determine if the addition of radium-223 dichloride to standard treatment is able to prolong life and to delay events specific for prostate cancer which has spread to the bone, such as painful fractures or bone pain which needs to be treated with an X-ray machine.

This study is a phase III multinational, multicenter,randomized, double blind, placebo controlled, study with a randomization allocation ratio of 1:1 (radium-223 dichloride plus abiraterone acetate plus prednisone/prednisolone: placebo plus abiraterone acetate plus prednisone/prednisolone). Until the final overall survival (OS) analysis, the study period consisted of screening / randomization, treatment, active follow-up with clinic visits, active follow-up without clinic visits, and longterm follow-up phases. Up until this point, subjects received study treatment (radium-223 dichloride or placebo in addition to abiraterone acetate plus prednisone / prednisolone for the first 6 cycles followed by abiraterone acetate plus prednisone / prednisolone thereafter) until an on-study SSE occurred (or other withdrawal criteria were met). After the final OS analysis (after implementation of Amendment 7), in order to reduce the burden to study subjects, evaluation of efficacy and exploratory endpoints will be discontinued, except for symptomatic skeletal event (SSE) and OS. Subjects who are discontinued from study treatment will initiate the long-term follow-up period; therefore, active follow-up periods will no longer be applicable. Subjects who are in active follow-up at the time of Amendment 7 is implemented should have the end of active follow-up completed (protocol driven decision) and should be directly transitioned into the extended safety follow-up study. Long term follow-up will continue until the subject dies, is lost to follow-up, withdraws informed consent, actively objects to collection of further data , or is transitioned to the extended safety follow-up study. Subjects will be followed for safety for up to 7 years, which eventually will be completed in this study or in the extended safety follow-up study.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Interventions

Radium-223 dichloride (Xofigo, BAY88-8223)DRUG

50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of NIST update) body weight, intravenous injection (IV-slow bolus), every 4 weeks for 6 cycles

Matching placebo (normal saline)DRUG

Intravenous injection ( IV-slow bolus), every 4 weeks for 6 cycles

AbirateroneDRUG

1000 mg once daily, oral, with best supportive care

Prednisone/PrednisoloneDRUG

5 mg twice daily, oral, with best supportive care

Eligibility

Sex: MALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Histologically confirmed adenocarcinoma of the prostate * Male subjects of age ≥ 18 years * Prostate cancer progression documented by prostate specific antigen (PSA) according to the Prostate Cancer Working Group 2 (PCWG2) criteria or radiological progression according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 * Two or more bone metastases on bone scan within 4 weeks prior to randomization with no lung, liver, other visceral and/or brain metastasis * Asymptomatic or mildly symptomatic prostate cancer * Subjects who received combined androgen blockade with an anti-androgen must have shown PSA progression after discontinuing the anti-androgen prior to enrollment * Maintenance of medical castration or surgical castration with testosterone less than 50 ng/dL (1.7nmol/L) * Eastern Cooperative Oncology Group performance status (ECOG PS) score 0 or 1 Exclusion Criteria: * Prior cytotoxic chemotherapy for the treatment of CRPC, including taxanes, mitoxantrone and estramustine * Any chronic medical condition requiring a higher dose of corticosteroid than 5 mg prednisone/prednisolone twice daily * Pathological finding consistent with small cell carcinoma of the prostate * History of visceral metastasis, or presence of visceral metastasis detected by screening imaging examinations * History of or known brain metastasis * Malignant lymphadenopathy exceeding 3 cm in short-axis diameter * Blood transfusion or erythropoietin stimulating agents prior 4 weeks of screening and during the whole screening period before randomization * Imminent spinal cord compression based on clinical findings and/or magnetic resonance imaging (MRI). Subjects with history of spinal cord compression should have completely recovered * Use of opiate analgesics for cancer-related pain, including codeine and dextropropoxyphene, currently or anytime during the 4- week period prior to randomization.

Locations (163)

Unnamed facility

Anchorage, Alaska, United States

Unnamed facility

Tucson, Arizona, United States

Unnamed facility

Oceanside, California, United States

Unnamed facility

Denver, Colorado, United States

Unnamed facility

Washington D.C., District of Columbia, United States

Unnamed facility

Outcomes

Primary Outcomes

Symptomatic Skeletal Event Free Survival (SSE-FS)

SSE-FS was defined as time (months) from randomization to the earliest of onset date of skeletal symptoms treated with external beam radiotherapy (EBRT), onset date of pathological bone fracture, onset date of spinal cord compression, procedure date of tumor-related orthopedic surgery, or death from any cause. Participants who died without prior SSE and ≥ 13 weeks after the last SSE assessment are censored at the last SSE assessment date. Participants alive at the survival cut-off date are censored at the last date known to be alive. Participants with multiple events are only counted for the category in which the first event occurred. If multiple SSE (component events) occur on the same date for 1 participant, the participant is only counted into 1 category in the order of: spinal cord compression \> bone fracture \> orthopedic surgery \> EBRT.

Time frame: From randomization until first onset of on-study symptomatic skeletal event (SSE) or death, up to 47 months

Secondary Outcomes

Overall Survival (OS)

OS was defined as the time (months) from the date of randomization to the date of death due to any cause. Participants alive at the survival cut-off date were censored at the last date known to be alive.

Time frame: From randomization until death from any cause, up to 67 months

Radiological Progression Free Survival (rPFS)

rPFS was defined as the time (months) from the date of randomization to the date of confirmed radiological progression or death (if death occurred before progression) based on independent assessment.

Time frame: From randomization until the date of confirmed radiological progression or death, up to 47 months

Time to Pain Progression

Time to pain progression was defined as the interval from randomization to the first date a participant experienced pain progression assessed by Brief Pain Inventory-Short Form and defined as: an increase of 2 or more points in the average worst pain score (WPS) from baseline observed at 2 consecutive evaluations ≥4 weeks apart or initiation of short- or long-acting opioid use for pain for participants with WPS 0 at baseline; an increase of 2 or more points in the average WPS from baseline observed at 2 consecutive evaluations ≥4 weeks apart and an average WPS of ≥4 OR initiation of short- or long-acting opioid use for pain for participants with WPS 1 to 3 at baseline. Participants without pain progression at end of study are censored at the last date known to have not progressed: last evaluation date for pain scores or last visit when recorded opiate use, whichever is last. Participants with no on-study assessment or no baseline assessment are censored at the date of randomization.

Time frame: From randomization until the date of pain progression based on pain score, up to 47 months

Time to Cytotoxic Chemotherapy

Time to cytotoxic chemotherapy is time (months) from randomization to the earliest date of the first cytotoxic chemotherapy. Participants who have not started cytotoxic chemotherapy during the study were censored at the last assessment date.

Time frame: From randomization until the date of first cytotoxic chemotherapy, up to 47 months

Time to Opiate Use for Cancer Pain

Time to opiate use for cancer pain was defined as the interval from the date of randomization to the date of opiate use.

Time frame: From randomization until the date of opiate use, up to 47 months

Number of Participants With Treatment-emergent Adverse Events

An adverse event (AE) was any untoward medical occurrence (i.e., any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a participant in the study. A serious adverse event (SAE) was any untoward medical occurrence that at any dose was resulting in death, was life-threatening, requires hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity. A treatment-emergent AEs (TEAEs) or serious TEAEs was defined as any event that started on or after the first dose of the study treatment and during the treatment period and was not a continuation of a pretreatment event or started before the first dose and worsened after the first dose or the treatment period. Drug-related TEAEs or serious TEAEs were those with "reasonable causal relationship" to the study treatment decided by the investigators.

Time frame: From start of study treatment until the end of the treatment period, up to 110 months

Number of Participants With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity

An adverse event (AE) was any untoward medical occurrence (i.e., any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a participant in the study. A serious adverse event (SAE) was any untoward medical occurrence that at any dose was resulting in death, was lifethreatening, requires hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity. A treatment-emergent AEs (TEAEs) or serious TEAEs was defined as any event that started on or after the first dose of the study treatment and during the treatment period and was not a continuation of a pretreatment event or started before the first dose and worsened after the first dose or the treatment period. Radium-223/placebo-related TEAEs or serious TEAEs were those with "reasonable causal relationship" to radium-223 or placebo decided by the investigators.

Time frame: From start of study treatment until the end of the treatment period, up to 110 months

Number of Participants With Any Treatment-emergent Additional Primary Malignancies

Treatment-emergent additional primary malignancies were adverse events identified as additional primary malignancies that occurred after start of study treatment until the end of the treatment period.

Time frame: From start of study treatment until the end of the treatment period, up to 110 months

Number of Participants With Treatment-emergent Bone Fractures

Treatment-emergent fractures were adverse events identified as fractures that occurred after start of study treatment until the end of the treatment period. All bone fractures and bone-associated events (e.g., osteoporosis) were reported as either AEs, or SAEs if the criteria of SAE were met, regardless of the investigator's causality assessment.

Time frame: From start of study treatment until the end of the treatment period, up to 110 months

Number of Participants With Post-treatment Adverse Events

An adverse event (AE) was any untoward medical occurrence (i.e., any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a participant in the study. Any bleeding event occurring during the study was not documented as an AE because this event was planned to be captured in the assessment of efficacy. AEs that started after the treatment period were defined as post-treatment AEs. Drug-related AEs were those with "reasonable causal relationship" to the study treatment decided by the investigators.